Disturbances in the hypothalamic-pituitary-thyroid axis (HPT) may have an etiologic role in patients with depression. Patients with very frequent recurrences and a tendency to go from mania to depression or vice-versa with only a brief intervening period of euthymic mood (rapid-cyclers) may suffer from an extreme form of this HPT disturbance seen in other depressives as indicated by tendency to develop frank and subclinical hypothyroism when treated with lithium carbonate. In the interval since our previous report, we have observed that the clinical response to thyroxine appears to be of relatively short duration (less than 6 months) and that relapse does not appear to be clearly related to decreases in thyroid hormones. Increases in doses resulted in partial clinical improvement in one case. Our preliminary results suggest that: (1) patients with very rapid mood cyclers are most likely to show improvement with thyroxine therapy, (2) clinical improvement was found only with hypermetabolic doses of thyroxine, (3) the duration of the response to thyroxine appears to be brief.